The present invention is concerned with a new process for the preparation of chloropyridine sulphonic acid chlorides.
Chloropyridine sulphonic acid chlorides serve as starting materials for the preparation of a series of pharmaceuticals with anti-inflammatory, anti-pyretic, cardiovascular, blood sugar-sinking and diuretic properties. Thus, for example, 4-chloropyridine-3-sulphonamide serves for the preparation of torasemide and thus of related blood sugar-sinking sulphonylureas which also inhibit inflammation and act diuretically (see J. Delarge Arzneimitt.-Forsch./Drug Res., 38(1), 1988, 144). The sulphonarnide is, in turn, prepared from 4-chloro-pyridine-3-sulphonic acid chloride.
In DE 25 14 334 A1 is described a process for the preparation of chlorinated pyridine-3-sulphonic acid derivatives, whereby, starting from 4-pyridinol-3-sulphonic acid chlorides, there first takes place the chlorination by means of a mixture of PCl.sub.5 and POCl.sub.3. The excess POCl.sub.3 and PCl.sub.5 is stripped off in a vacuum, and the remaining residue is worked up in a complicated way in several steps. Similar processes with the use of PCl.sub.5 /POCl.sub.3 are known from the literature (see L. Thunus, Annales pharmaceutiques francais, 33, 1975, 487; Tullio et al., Tetrahedron, 51, 1995, 3221, as well as EP 0 618 209 A1, DE 25 14 334 and FR 88,352).
The chlorination thereby takes place in one step by the substitution of the OH group on the ring and in the sulphonic acid residue with formation of hydrogen chloride and POCl.sub.3. As halogenation agent, there serves exclusively phosphorus pentachloride, always used in excess, whereas phosphorus oxychloride is used as solvent since it is always obtained in the reaction mixture in the case of the reaction of the phosphorus pentachloride. Phosphorus oxychloride does not itself lead to the chlorination. After the reaction, it can be removed from the mixture by distillation and, without further purification steps, can be used again for the next batch.
Other chlorination agents, for example thionyl chloride, sulphuryl chloride or also phosphorus tri-chloride, essentially only replace the phenolic OH group and are, therefore, not suitable for the reaction.
It is a disadvantage of the known processes that, in the case of batches of large-scale size, the starting materials cannot be mixed together from the beginning, since this can lead to a longer controllable course of the reaction with a vigorous evolution of gas. Therefore, according to the prior art, there takes place a slow, measured addition of the acid to the boiling mixture of phosphorus pentachloride and phosphorus oxychloride, as well as possibly an after-dosing of PCl.sub.5.
However, the dosing in of the solid reactants present in solid state (hydroxypyridine-sulphonic acid and PCl.sub.5) leads to considerable problems. There are several possibilities for the addition. Either the reactors must be opened, whereby the aggressive chemicals HCl and POCl.sub.3 are liberated, or the addition takes place with the help of transport means for solid materials, for example transport screws. In this case, too, problems arise since the contact of the solid substances with the boiling POCl.sub.3 leads to no longer transportable adhesions and encrustations.
Since phosphorus pentachloride is always used in excess, unreacted PCl.sub.5 sub-limes in the case of the distilling off of the solvent (POCl.sub.3) and leads to encrustations and stoppages of the cooler. Furthermore, additional reaction steps for the decomposition of the excess halogenation agent by hydrolysis on ice, possible neutralisation with alkali and subsequent extraction are necessary. The yields of the known processes lie at about 70%.